title: Synthesis and biological evaluation of fatty acyl ester derivatives of 2',3'-didehydro-2',3'-dideoxythymidine.
abstract: A number of 5'-O-fatty acyl derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T) were synthesized and evaluated for anti-HIV activities against cell-free and cell-associated virus, cellular cytotoxicity, and cellular uptake studies. The conjugates were found to be more potent than d4T. Among these conjugates, 5'-O-12-azidododecanoyl derivative of d4T (2), displaying EC(50) = 3.1-22.4 μM, showed 4- to 9-fold higher activities than d4T against cell-free and cell-associated virus. Cellular uptake studies were conducted on CCRF-CEM cell line using 5(6)-carboxyfluorescein derivatives of d4T attached through β-alanine (9) or 12-aminododecanoic acid (10) as linkers. The fluorescein-substituted analog of d4T with long chain length (10) showed 12- to 15-fold higher cellular uptake profile than the corresponding analog with short chain length (9). These studies reveal that conjugation of fatty acids to d4T enhances the cellular uptake and anti-HIV activity of stavudine.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.forename: Kelly
authors.initials: K
authors.lastname: Loethan
authors.forename: Deendayal
authors.initials: D
authors.lastname: Mandal
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D002474:Cell-Free System; D004952:Esters / Q000737:chemistry*; D006801:Humans; D008856:Microscopy, Fluorescence; D018119:Stavudine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D004952:Esters; D018119:Stavudine